Parkinson's disease: A disorder due to nigral glutathione deficiency?

Perry, Thomas L.; Godin, David V.; Hansen, Shirley

doi:10.1016/0304-3940(82)90390-1

Cited by 728 publications

(326 citation statements)

References 21 publications

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“…Levels of GSSG were about 2.3% of the total glutathione. These results conflict with those indicating that about 90% of the glutathione in the substantia nigra is in the oxidized form [10]. This study found that most of the total glutathione in various areas of the human brain is in the form of GSSG [10], whereas other authors described GSSG as 1.2% or less of total glutathione in autopsy specimens of human brain and in fresh samples of monkey brain [16].…”

contrasting

confidence: 81%

“…These mechanisms, however, may be impaired in Parkinson's disease, e.g. reduced activity ofcatalase, peroxidase and glutathione peroxidase and diminished concentrations of GSH have been found in the substantia nigra in Parkinson's disease [1,7,10,12]. GSH in the substantia nigra and enzymes that utilize GSH for free radical detoxification, such as glutathione peroxidase and glutathione-S-transferase, probably play an important role in protecting dopaminergic nigrostriatal neurones from damage by 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), or from other MPTP-like neurotoxins which may cause Parkinson's disease in humans.…”

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confidence: 99%

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Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease

Sofić

Lange

Jellinger

et al. 1992

Neuroscience Letters

552

312

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Reduced and oxidized glutathione concentrations in post-mortem brain tissue from the substantia nigra of control subjects and patients with neuropathologically confirmed Parkinson's disease were measured by a coulometric method using high-pressure liquid chromatography and electrochemical detection. Reduced glutathione concentrations were decreased in the substantia nigra of parkinsonian patients compared with controls. Differences in the concentration of oxidized glutathione and in the percentage of oxidized glutathione of the total gtutathione were not observed between parkinsonian and control subjects. The finding that oxidized glutathione is not decreased in Parkinson's disease suggests that the decrease in reduced glutathione is not exclusively the consequence of neuronal loss in the substantia nigra but may indicate a state of oxidative stress.

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contrasting

confidence: 81%

mentioning

confidence: 99%

Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease

Sofić

Lange

Jellinger

et al. 1992

Neuroscience Letters

552

312

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“…GSH is also the co-substrate for several key cellular antioxidative and phase 2 enzymes. In this context, early depletion of cellular GSH and the accompanying oxidative stress in substantia nigra are important biochemical features of PD (Perry et al, 1982;Perry and Yong, 1986;Sofic et al, 1992;Spencer et al, 1995;Sechi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

et al. 2008

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Evidence suggests oxidative and electrophilic stress as a major factor contributing to the neuronal cell death in neurodegenerative disorders, especially Parkinson's disease. Consistent with this concept, administration of exogenous antioxidants has been shown to be protective against oxidative/ electrophilic neurodegeneration. However, whether induction of endogenous antioxidants and phase 2 enzymes by the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T) in neuronal cells also affords protection against oxidative and electrophilic neurocytotoxicity has not been carefully investigated. In this study, we showed that incubation of SH-SY5Y neuroblastoma cells or primary human neurons with micromolar concentrations (10-100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two crucial cellular defenses against oxidative and electrophilic stress. D3T treatment also caused increases in mRNA expression of γ-glutamylcysteine ligase catalytic subunit and NQO1 in SH-SY5Y cells. In addition, D3T treatment of the neuronal cells also resulted in a marked elevation of GSH content in the mitochondrial compartment. To determine the protective effects of the D3T-induced cellular defenses on neurotoxicant-elicited cell injury, SH-SY5Y cells were pretreated with D3T for 24 h and then exposed to dopamine, 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), or H 2 O 2 , agents that are known to be involved in neuron degeneration. We observed that D3T-pretreatment of SH-SY5Y cells led to significant protection against the cytotoxicity elicited by the above neurotoxicants. Similar neurocytoprotective effects of D3T-pretreatment were also observed in primary human neurons exposed to 6-OHDA or HNE. Taken together, this study demonstrates that D3T potently induces neuronal cellular GSH and NQO1 as well as mitochondrial GSH, and that such upregulated endogenous defenses are accompanied by increased resistance to oxidative and electrophilic neurocytotoxicity.

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“…28,29 Traditionally, biochemical assays of the ratio of cellular thiols to disulfides, or more specifically the reduced to oxidized glutathione ratio, have been used as markers of peroxidative stress within brain tissue. [2][3][4]9,10,14,16,18 However, further research in this field has been hindered by the lack of tools to show the distribution of altered sulfur redox. For example, there is no isotope of sulfur for which NMR or MRI measurements are practical.…”

mentioning

confidence: 99%

X-ray Absorption Spectroscopy at the Sulfur K-Edge: A New Tool to Investigate the Biochemical Mechanisms of Neurodegeneration

Hackett

Smith

Paterson

et al. 2012

ACS Chem. Neurosci.

100

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Sulfur containing molecules such as thiols, disulfides, sulfoxides, sulfonic acids, and sulfates may contribute to neurodegenerative processes. However, previous study in this field has been limited by the lack of in situ analytical techniques. This limitation may now be largely overcome following the development of synchrotron radiation X-ray absorption spectroscopy at the sulfur K-edge, which has been validated as a novel tool to investigate and image the speciation of sulfur in situ. In this investigation, we build the foundation required for future application of this technique to study and image the speciation of sulfur in situ within brain tissue. This study has determined the effect of sample preparation and fixation methods on the speciation of sulfur in thin sections of rat brain tissue, determined the speciation of sulfur within specific brain regions (brain stem and cerebellum), and identified sulfur specific markers of peroxidative stress following metal catalyzed reactive oxygen species production. X-ray absorption spectroscopy at the sulfur K-edge is now poised for an exciting new range of applications to study thiol redox, methionine oxidation, and the role of taurine and sulfatides during neurodegeneration.

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Parkinson's disease: A disorder due to nigral glutathione deficiency?

Cited by 728 publications

References 21 publications

Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease

Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

X-ray Absorption Spectroscopy at the Sulfur K-Edge: A New Tool to Investigate the Biochemical Mechanisms of Neurodegeneration

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